|
 
 |
| ORIGINAL ARTICLE |
|
| Year : 2016 | Volume
: 11
| Issue : 4 | Page : 192-196 |
|
Test–retest reliability and correlates of 6-minute walk test in patients with primary osteoarthritis of knees
Mahamed Ateef1, Sivachidambaram Kulandaivelan2, Shaziya Tahseen1
1 Department of Physiotherapy, Majmaah University, Al Majmaah, Kingdom of Saudi Arabia
2 Department of Physiotherapy, GJUST, Hisar, Haryana, India
| Date of Web Publication | 8-Nov-2016 |
Correspondence Address:
Dr. Sivachidambaram Kulandaivelan
Department of Physiotherapy, GJUST, Hisar - 125 001, Haryana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-3698.192668
Background: In the assessment of primary osteoarthritis (OA) of knees several clinical tool including 6 minutes walk test (6 MWT) are used. The objective of this study was to to analyze the test-retest reliability of 6 MWT and its correlation with various parameters.
Methods: Eighty patients (age, 56-79 years) with OA of knees met the inclusion criteria. Demographic and clinical characteristics including radiological severity of OA (by X-ray K/L grading) were recorded. Patients filled in the knee injury and osteoarthritis outcome score (KOOS) questionnaire. All patients performed 6 MWT twice with at least 48 h gap in-between.
Results: Test–retest reliability of 6 MWT in primary OA knee patients was excellent with ICC 0.991 (95% confidence interval was 0.986–0.994). 6 MWT had a weak correlation with KOOS-symptom and KOOS-activities of daily living (rho = 0.397 and 0.364 respectively), a strong correlation with KOOS-pain and KOOS-sports (rho = 0.605 and 0.521 respectively), and a very strong correlation with KOOS-quality of life (rho = 0.758). It had a weak correlation with age and height (r = 0.497 and 0.302), a strong correlation with VAS, weight, and BMI (rho = −0.655, r = −0.510, and − 0.691, respectively), and a very strong correlation with disease severity (rho = −0. 849).
Conclusion: 6 MWT was a reliable test and positively correlated with all KOOS subscales and negatively correlated with other parameters except height in primary OA knee. Keywords: Intraclass correlation coefficient, knee injury and osteoarthritis outcome score, knee outcome measure
How to cite this article:
Ateef M, Kulandaivelan S, Tahseen S. Test–retest reliability and correlates of 6-minute walk test in patients with primary osteoarthritis of knees. Indian J Rheumatol 2016;11:192-6 |
How to cite this URL:
Ateef M, Kulandaivelan S, Tahseen S. Test–retest reliability and correlates of 6-minute walk test in patients with primary osteoarthritis of knees. Indian J Rheumatol [serial online] 2016 [cited 2022 Sep 28];11:192-6. Available from: https://www.indianjrheumatol.com/text.asp?2016/11/4/192/192668 |
| Introduction | |  |
Osteoarthritis (OA), is one of the most common articular conditions that affect older adults. Old age and increased weight cause OA knee that results in pain and weakened muscles around the joint. It has a major impact on both physical (objective) and psychological (subjective) health leading to more disability. Weak muscles decrease aerobic capacity and reduce tolerance for activities of daily living (ADL), including walking. Walking is the activity most commonly reported as difficult by those with knee OA.[1] It can also be reduced as an indirect consequence to mechanical complications.[2] Compared to healthy adults, people with knee OA walks more slowly due to a shorter stride length, decreased cadence, and pain.[3],[4]
There are two types of mobility outcome measures to be considered: The individual's assessment of his/her own physical function (self-reported) and observed physical performance (performance). Self-reported measures, subjective, are sometimes regarded as less quantifiable than objective measures. Some of the commonly used self-reported measures in OA knee are Knee injury and Osteoarthritis Outcome Score (KOSS), Short Form-36 (SF-36), etc., Clinicians most often measure performance directly using performance-based measurements such as the 6-min walk test (6 MWT) and timed up and go test, and stair climb test. All these tests, both subjective as well as objective, are inexpensive and easy to administer. They give valuable information such as disease severity and disease prognosis to the clinician.
6 MWT not only assess the patient's walking ability, but also gives an indication of the endurance level of the individual. Hence, it is an excellent functional outcome measure for OA knee that is recommended by American College of Rheumatology (ACR). Its reliability was determined in elderly population, postsurgical intervention of hip and knee joint in Western population,[5],[6] but not yet been appraised in the Indian population.
Thus, the primary objective of the present study was to assess the test–retest reliability of 6 MWT. Secondary objectives were to assess the correlation of 6 MWT with anthropometric variables (age, height, weight, and body mass index [BMI]), subscales of self-reported questionnaire (KOOS), visual analog scale (VAS), and disease severity in Indian OA knee patients.
| Methodology | | |
The study was conducted in different hospitals in Hyderabad, India, during April and May 2013.
Data were taken from the OA knee individuals who were diagnosed based on the ACR criteria [7] which were supported by radiographic evidence. Individuals with any evidence of secondary OA, inflammatory arthritis, any lower extremity muscle strain, ligament sprain, and those with neurologic conditions including low Mini-Mental examination score were excluded from the study. Other exclusion criteria were modified from Focht et al.[8] All exclusion criteria were asked verbally except Mini–Mental examination score.
The BMI (in kg/m 2) was calculated from measured height and weight. Pain was measured by visual analogue scale (VAS) 100 mm.
Radiographs were assessed for the presence of joint space narrowing, marginal spur formation, and subchondral cyst formation. The radiographs were evaluated by a blinded experienced radiologist using the Kellgren and Lawrence (KL) grading, in which 0 refers no radiographic OA and 4 refers to severe OA. The KL method of classification was used where grade 0 = normal, 1 = doubtful osteophyte, 2 = definite osteophyte, 3 = moderate joint space narrowing, and 4 = severe joint space narrowing. The intrarater reliability of KL grading has been established to be high.[9]
Knee injury and osteoarthritis outcome score (KOOS) is a most commonly used outcome measure tool. It is an extension of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Initially developed for the young and/or physically active patients with knee injury and/or OA,[10] it is also valid for elderly patients.[11]
6 MWT was conducted in a well-ventilated, quiet, hard, and flat surface hallway with at least 20 m distance in between. Two cones were placed 20 m apart, and the patients were instructed to walk at their own pace to cover maximum distance in 6 min. Participants were not allowed to carry a watch and were not provided any feedback during the test. Verbal encouragement was avoided. The test was terminated if the person reported chest pain, intolerable shortness of breath, leg cramps, and appeared diaphoresis or pale/ashen appearance.[12] 6 MWT was administered twice with at least 48 h gap in-between.
Data were presented in mean ± standard deviation (SD), standard error of mean, and 95% confidence interval (95% CI) as descriptive analysis. Intraclass correlation coefficient (ICC) was used to see the test–retest reliability of 6 MWT. Unpaired t-test was used to observe gender difference. One-way ANNOVA was used to see the content validity of 6 MWT with KL grading (disease severity). Pearson's correlation (r) test and Spearman correlation (rho) test were used for analyzing continuous and ordinal/interval scale variables, respectively, with 6 MWT. All correlation coefficients were classified as 0–0.3 - none; 0.31–0.5 - weak; 0.51–0.7 - strong; 0.71–0.9 - very strong; and >0.9 - excellent.[13]
| Results | | |
A consecutive sample of 80 (29 males and 51 females) was taken out of 96 eligible patients. Sixteen patients refused to give consent, making it 83% acceptance rate. All refused patients were males, and the reason given was lack of time and/or long distance of testing center from home. Basic characteristics of the sample (mean ± SD) were 50.68 ± 15.51 years, 1.59 ± 0.11 m, 72.72 ± 14.98 kg, and 28.81 ± 4.86 kg/m 2 for age, height, weight, and BMI, respectively.
[Table 1] shows that there was a significant sex difference in 6 MWT. Males covered 20% more distance than females (95% CI: 30.67 m and − 104.30 m, P < 0.001). There was an excellent test–retest reliability of 6 MWT. Compared to the 1st test, there was only <3% improvement in the 2nd test. | Table 1: Gender difference in 6-min walk test and test-retest reliability of 6-min walk test in primary osteoarthritis knee patients (n=80)
Click here to view |
[Table 2] shows ANNOVA along with post hoc analysis of 6 MWT with KL grading (disease severity) (content validity). It is expected that as the disease progress, that is evident from X-ray, 6 MWT should decrease. The result confirmed this hypothesis and there was a significant difference between disease severity grading. All the subsequent grading showed a significant reduction in 6 MWT except Grade 1 and 2. An average of 54.42 m difference was found between the grading (range: 30.65 m to 72.46 m). | Table 2: Analysis of variance table for disease severity with post hoc analysis (content validity) of 6-min walk test in primary osteoarthritis knee patients (n=80)
Click here to view |
6 MWT had a weak-to-strong correlation with subscales of self-reported questionnaire KOOS [Table 3] (concurrent validity). It has a weak negative correlation with symptom and ADL subscales, strong negative correlation with pain and sports subscales, and very strong negative correlation with QOL subscales. | Table 3: Correlation of 6-min walk test with knee injury and osteoarthritis outcome score subscales (concurrent validity) in primary osteoarthritis knee patients
Click here to view |
[Table 4] shows a correlation between 6 MWT and some OA determinants. 6 MWT has a weak correlation with age and height; a strong negative correlation with weight, BMI, and pain; and a very strong negative correlation with disease severity (KL grading). | Table 4: Correlation between 6-min walk test and some osteoarthritis knee determinants
Click here to view |
| Discussion | | |
The primary objective of the present study was to assess the test–retest reliability of 6 MWT in Indian primary OA knee patients. The result shows an excellent reliability in this population. These results supports observations noted in two previous studies.[5],[6] Long-term excellent reliability (ICC 0.94) was reported in end-stage hip and knee OA.[6] Rejeski et al.[5] reported two weekly test–retest reliability of 0.87 for patients with knee OA.
There was <3% improvement in 2nd time over 1st time in this study. Previous studies show <4%–<10% improvement in 2nd time.[14],[15],[16] The reason for this improvement is familiarization of procedure, learning effect, and self-motivation to do better than previous one.
Incidence of OA knee is more common in females than males.[17] The result reveals that females covered 20-25% less distance than their male counterparts. This was also noted in the studies by Ateef et al.[18] and Longerstedt et al.[19] who presented similar sex difference in walking distance among moderate-to-severe OA knee patients. The reasons for this discrepancy are weaker knee muscles, shorter stride length, higher BMI, and lower gait speed (slower walking) in female OA knee patients.
6 MWT had a favorable correlation with all subscales of KOOS in our previous study.[20] The results of the present studies are also similar to that study.
6 MWT strongly correlated with KOOS-Pain subscale and VAS pain scale. Similar findings were also noted in a study by Stratford et al.[21] who found 0.74 correlation between VAS and 6MWT in OA patients. However, literature shows a weak correlation of 6 MWT with pain subscales at −0.39[22] and −0.205.[23] Pain is the cardinal sign of OA knee and inversely affects the walking distance. People with knee pain walk slowly which in turn increases joint loading that deteriorate the condition further.[24],[25]
6 MWT is strongly correlated with KOOS-Sports subscale but weakly correlated with KOOS-ADL subscale. Literature supports a strong correlation of 6 MWT with WOMAC physical function subscale in OA knee patients (r = −0.54[22] and r = −0.646[23]). As factors other than simple walking alone influence physical function, the relationship between self-reported physical function and performance measures, such as the 6-min walk, is low.[26]
There was a negative correlation between age and 6 MWT. Age negatively correlated walking distance (r = −0.41[27] and r = −0.249[28]) in knee OA patients. It is also supported by healthy elder population (r = −0.51[14] and r =−0.42[29]), adult population (r − 0.36[15] and r = −0.66[30]), and women [31] (r = −0.27). OA is a degenerative condition that worsens as the age progress; hence, there was a negative correlation between age and 6 MWT. Other reasons include muscular atrophy, slow reaction time, slow gait speed, and muscle weakness, associated with age.
There was a weak positive correlation between height and 6 MWT. This is supported in healthy older adults (r = 0.54[14]) and healthy adult population (r = 0.35[15] and r = 0.42[30]). The reason for positive correlation between height and 6 MWT is that as the height increases, stride length of the individual also increases. This will increase the overall walking distance.
There was a strong negative correlation between weight and 6 MWT. This is supported in OA knee patients [32] (r = −0.528) and healthy women [31] (r = −0.68). The reason for negative correlation is as weight increases gait speed decreases and joint loading also increases, causing more damage to the joint.[24],[25]
There was a strong negative correlation between BMI and 6 MWT. This is supported in Indian OA knee patients [33] (r = −0.69), Indian older adults [34] (r = −0.81), and healthy women [31] (r = −-0.77). Maly et al.[35] reported a negative correlation between 6MWT and BMI (r = −-0.39). The possible reason for less value than the present study may be explained by age, i.e. mean age reported by Maly et al.[35] was 68.3 whereas the mean age of the present study was 50.68. Our previous studies [28],[33] explained that as the age progresses, even patients with less BMI get OA easily that might affect the r value.
| Conclusion | | |
6 MWT is a reliable objective measurement of OA knee in Indian population. It has good content and concurrent validity. Hence, it can be used as an outcome measure in rehabilitation protocols.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, Wilson PW, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health 1994;84:351-8.  |
| 2. | Messier SP. Osteoarthritis of the knee and associated factors of age and obesity: Effects on gait. Med Sci Sports Exerc 1994;26:1446-52. |
| 3. | Gök H, Ergin S, Yavuzer G. Kinetic and kinematic characteristics of gait in patients with medial knee arthrosis. Acta Orthop Scand 2002;73:647-52. |
| 4. | Kaufman KR, Hughes C, Morrey BF, Morrey M, An KN. Gait characteristics of patients with knee osteoarthritis. J Biomech 2001;34:907-15. |
| 5. | Rejeski WJ, Ettinger WH Jr., Schumaker S, James P, Burns R, Elam JT. Assessing performance-related disability in patients with knee osteoarthritis. Osteoarthritis Cartilage 1995;3:157-67. |
| 6. | Kennedy DM, Stratford PW, Wessel J, Gollish JD, Penney D. Assessing stability and change of four performance measures: A longitudinal study evaluating outcome following total hip and knee arthroplasty. BMC Musculoskelet Disord 2005;6:3. |
| 7. | Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 1986;29:1039-49. |
| 8. | Focht BC, Garver MJ, Devor ST, Dials J, Rose M, Lucas AR, et al. Improving maintenance of physical activity in older, knee osteoarthritis patients trial-pilot (IMPACT-P): Design and methods. Contemp Clin Trials 2012;33:976-82. |
| 9. | Sun Y, Günther KP, Brenner H. Reliability of radiographic grading of osteoarthritis of the hip and knee. Scand J Rheumatol 1997;26:155-65. |
| 10. | Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee injury and Osteoarthritis Outcome Score (KOOS) – Development of a self-administered outcome measure. J Orthop Sports Phys Ther 1998;28:88-96. |
| 11. | Roos EM, Toksvig-Larsen S. Knee injury and Osteoarthritis Outcome Score (KOOS) – Validation and comparison to the WOMAC in total knee replacement. Health Qual Life Outcomes 2003;1:17. |
| 12. | ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7. |
| 13. | Gudbergsen H, Bartels EM, Krusager P, Wæhrens EE, Christensen R, Danneskiold-Samsøe B, et al. Test-retest of computerized health status questionnaires frequently used in the monitoring of knee osteoarthritis: A randomized crossover trial. BMC Musculoskelet Disord 2011;12:190. |
| 14. | Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999;14:270-4. |
| 15. | Poh H, Eastwood PR, Cecins NM, Ho KT, Jenkins SC. Six-minute walk distance in healthy Singaporean adults cannot be predicted using reference equations derived from Caucasian populations. Respirology 2006;11:211-6. |
| 16. | Hanson LC, McBurney H, Taylor NF. The retest reliability of the six-minute walk test in patients referred to a cardiac rehabilitation programme. Physiother Res Int 2012;17:55-61. |
| 17. | Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D, Jones G. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage 2005;13:769-81. |
| 18. | Ateef M, Kulandaivelan S, Shaziya T. Evaluation of gender related functional status in Indian primary knee osteoarthritis population. Indian J Health Wellbeing 2013;4:305-7. |
| 19. | Logerstedt DS, Zeni J Jr., Snyder-Mackler L. Sex differences in patients with different stages of knee osteoarthritis. Arch Phys Med Rehabil 2014;95:2376-81. |
| 20. | Sivachidambaram K, Ateef M, Tahseen S. Correlation of self-reported questionnaire (KOOS) with some objective measures in primary OA knee patients. ISRN Rheumatol 2014;2014:301485. |
| 21. | Stratford PW, Kennedy DM, Woodhouse LJ. Performance measures provide assessments of pain and function in people with advanced osteoarthritis of the hip or knee. Phys Ther 2006;86:1489-96. |
| 22. | Maly MR, Costigan PA, Olney SJ. Determinants of self-report outcome measures in people with knee osteoarthritis. Arch Phys Med Rehabil 2006;87:96-104. |
| 23. | Sutbeyaz ST, Sezer N, Koseoglu BF, Ibrahimoglu F, Tekin D. Influence of knee osteoarthritis on exercise capacity and quality of life in obese adults. Obesity (Silver Spring) 2007;15:2071-6. |
| 24. | Purser JL, Golightly YM, Feng Q, Helmick CG, Renner JB, Jordan JM. Association of slower walking speed with incident knee osteoarthritis-related outcomes. Arthritis Care Res (Hoboken) 2012;64:1028-35. |
| 25. | White DK, Niu J, Zhang Y. Is symptomatic knee osteoarthritis a risk factor for a trajectory of fast decline in gait speed? Results from a longitudinal cohort study. Arthritis Care Res (Hoboken) 2013;65:187-94. |
| 26. | Stratford PW, Kennedy DM. Performance measures were necessary to obtain a complete picture of osteoarthritic patients. J Clin Epidemiol 2006;59:160-7. |
| 27. | Marks R. Obesity profiles with knee osteoarthritis: Correlation with pain, disability, disease progression. Obesity (Silver Spring) 2007;15:1867-74. |
| 28. | Ateef MD, Tahseen S, Kulandaivelan S. Influence of age on self-reported and actual physical performance measures in primary knee osteoarthritis. Indian J Health Wellbeing 2012;3:1087-9. |
| 29. | Bautmans I, Lambert M, Mets T. The six-minute walk test in community dwelling elderly: Influence of health status. BMC Geriatr 2004;4:6. |
| 30. | Soaresa MR, Pereira CA. Six-minute walk test: Reference values for healthy adults in Brazil. J Bras Pneumol 2011;37:576-83. |
| 31. | Hulens M, Vansant G, Claessens AL, Lysens R, Muls E. Predictors of 6-minute walk test results in lean, obese and morbidly obese women. Scand J Med Sci Sports 2003;13:98-105. |
| 32. | Miller GD, Nicklas BJ, Davis C, Loeser RF, Lenchik L, Messier SP. Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis. Obesity (Silver Spring) 2006;14:1219-30. |
| 33. | Mahamed A, Kulandaivelan S, Tahseen S. Impact of obesity on functional status in primary knee osteoarthritis. Int J Pharm Health Care Res 2013;1:53-8. |
| 34. | Sarkar A, Razdan S, Sharma H, Bhatia S, Bansal N, Kuhar S. Assessment of the cardiovascular fitness of non-exercising subjects using six minute walk test. Indian J Physiother Occup Ther 2009;3:10-3. |
| 35. | Maly MR, Costigan PA, Olney SJ. Contribution of psychosocial and mechanical variables to physical performance measures in knee osteoarthritis. Phys Ther 2005;85:1318-28. |
[Table 1], [Table 2], [Table 3], [Table 4]
| This article has been cited by | | 1 |
Effect of High-Power Laser Therapy Versus Shock Wave Therapy on Pain and Function in Knee Osteoarthritis Patients: A Randomized Controlled Trial |
|
| Mohamed Serag Eldein Mahgoub Mostafa, Hamada Ahmed Hamada, Ahmed Mahmoud Kadry, Samah Saad Zahran, Nesma Ahmed Helmy | | Photobiomodulation, Photomedicine, and Laser Surgery. 2022; | | [Pubmed] | [DOI] | | | 2 |
The combination of osteoporosis and low lean mass correlates with physical function in end-stage knee osteoarthritis: A retrospective observational study |
|
| So Young Lee, Bo Ryun Kim, Sang Rim Kim, Jun Hwan Choi, Eui Jin Jeong, Jinseok Kim | | Medicine. 2022; 101(31): e29960 | | [Pubmed] | [DOI] | | | 3 |
Effects of Hip Bracing on Gait Biomechanics, Pain and Function in Subjects With Mild to Moderate Hip Osteoarthritis |
|
| Hannah Steingrebe, Bernd J. Stetter, Stefan Sell, Thorsten Stein | | Frontiers in Bioengineering and Biotechnology. 2022; 10 | | [Pubmed] | [DOI] | | | 4 |
A Systematic Review of Psychometric Properties of Knee-Related Outcome Measures Translated, Cross-Culturally Adapted, and Validated in Arabic Language |
|
| Mahamed Ateef, Mazen Alqahtani, Msaad Alzhrani, Abdulaziz A. Alkathiry, Ahmad Alanazi, Shady Abdullah Alshewaier | | Healthcare. 2022; 10(9): 1631 | | [Pubmed] | [DOI] | | | 5 |
Knee Injury and Osteoarthritis Outcome Score Patellofemoral Questionnaire: Psychometric Properties among Females of Kingdom of Saudi Arabia |
|
| Msaad Alzhrani | | International Journal of Environmental Research and Public Health. 2022; 19(10): 6058 | | [Pubmed] | [DOI] | | | 6 |
Measurement properties of the Knee Injury and Osteoarthritis Outcome Score Patello-Femoral questionnaire in Saudi Arabians |
|
| Mahamed Ateef | | PeerJ. 2020; 8: e9323 | | [Pubmed] | [DOI] | | | 7 |
Does tension applied in kinesio taping affect pain or function in older women with knee osteoarthritis? A randomised controlled trial |
|
| Yago Tavares Pinheiro,Germanna Medeiros Barbosa,Hilmaynne Renaly Fonseca Fialho,César Augusto Medeiros Silva,Jaciara de Oliveira Anunciação,Hugo Jário de Almeida Silva,Marcelo Cardoso de Souza,Caio Alano de Almeida Lins | | BMJ Open. 2020; 10(12): e041121 | | [Pubmed] | [DOI] | | | 8 |
Measures of Physical Performance |
|
| Grace Coleman,Fiona Dobson,Rana S. Hinman,Kim Bennell,Daniel K. White | | Arthritis Care & Research. 2020; 72(S10): 452 | | [Pubmed] | [DOI] | | | 9 |
Validity of an instrumented knee brace compared to 3D motion navigation: a cadaveric investigation |
|
| Reneaud Nicolas,Pierre Emma,Zory Raphaël,Chorin Frédéric,Thomas Luc,Chavet Pascale,Coyle Thelma,Truchet Eric,Puech Stephane,Ollivier Matthieu,Chabrand Patrick,Gerus Pauline | | Measurement. 2020; : 108590 | | [Pubmed] | [DOI] | | | 10 |
Cross-Cultural Validation of Urdu Version KOOS in Indian Population with Primary Knee Osteoarthritis |
|
| Mahamed Ateef,Sivachidambaram Kulandaivelan,Mazen Alqahtani | | International Journal of Rheumatology. 2017; 2017: 1 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
Search Pubmed for